EP0519748B1 - Peptidylderivate als Inhibitoren von Interleukin-1B-konvertierenden Enzymen - Google Patents

Peptidylderivate als Inhibitoren von Interleukin-1B-konvertierenden Enzymen Download PDF

Info

Publication number
EP0519748B1
EP0519748B1 EP92305670A EP92305670A EP0519748B1 EP 0519748 B1 EP0519748 B1 EP 0519748B1 EP 92305670 A EP92305670 A EP 92305670A EP 92305670 A EP92305670 A EP 92305670A EP 0519748 B1 EP0519748 B1 EP 0519748B1
Authority
EP
European Patent Office
Prior art keywords
alkyl
aryl
hydroxy
amino
substituted
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
Application number
EP92305670A
Other languages
English (en)
French (fr)
Other versions
EP0519748A3 (en
EP0519748A2 (de
Inventor
Kevin T. Chapman
Nancy A. Thornberry
Herb G. Bull
Jeffrey R. Weidner
Malcolm Maccoss
Adnan M. Mjalli
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Merck and Co Inc
Original Assignee
Merck and Co Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Merck and Co Inc filed Critical Merck and Co Inc
Publication of EP0519748A2 publication Critical patent/EP0519748A2/de
Publication of EP0519748A3 publication Critical patent/EP0519748A3/en
Application granted granted Critical
Publication of EP0519748B1 publication Critical patent/EP0519748B1/de
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
    • C07K5/0202—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -NH-X-X-C(=0)-, X being an optionally substituted carbon atom or a heteroatom, e.g. beta-amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/45—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
    • C07C233/46—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • C07C233/47—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/45—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
    • C07C233/46—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • C07C233/51—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to an acyclic carbon atom of a carbon skeleton containing six-membered aromatic rings

Definitions

  • This invention relates to substituted peptidyl derivatives useful in the treatment of inflammation in lung, central nervous system, kidney, joints, endocardium, pericardium, eyes, ears, skin, gastrointestinal tract and urogenital system. More particularly, this invention relates to substituted peptidyl lactones and open forms thereof that are useful inhibitors of interleukin-1 ⁇ converting enzyme (ICE).
  • Interleukin-1 ⁇ converting enzyme ICE has been identified as the enzyme responsible for converting precursor interleukin-1 ⁇ (IL-1 ⁇ ) to biologically active IL-1 ⁇ .
  • IL-1 Mammalian interleukin-1
  • IL-1 is an immunoregulatory protein secreted by cell types as part of the inflammatory response.
  • the primary cell type responsible for IL-1 production is the peripheral blood monocyte.
  • Other cell types have also been described as releasing or containing IL-1 or IL-1 like molecules. These include epithelial cells (Luger, et al., J. Immunol. 127: 1493-1498 (1981), Le et al., J. Immunol. 138: 2520-2526 (1987) and Lovett and Larsen, J. Clin. Invest. 82: 115-122 (1988), connective tissue cells (Ollivierre et al., Biochem. Biophys. Res. Comm.
  • Biologically active IL-1 exists in two distinct forms, IL-1 ⁇ with an isoelectric point of about pI 5.2 and IL-1 ⁇ with an isoelectric point of about 7.0 with both forms having a molecular mass of about 17,500 (Bayne et al., J. Esp. Med. 163: 1267-1280 (1986) and Schmidt, J. Esp. Med. 160: 772 (1984).
  • the polypeptides appear evolutionarily conserved, showing about 27-33% homology at the amino acid level (Clark et al., Nucleic Acids Res. 14: 7897-7914 (1986).
  • Mammalian IL-1 ⁇ is synthesized as a cell associated precursor polypeptide with a molecular mass of about 31.4 kDa (Limjuco et al., Proc. Natl. Acad. Sci USA 83: 3972-3976 (1986).
  • Precursor IL-1 ⁇ is unable to bind to IL-1 receptors and is biologically inactive (Mosley et al., J. Biol. Chem. 262: 2941-2944 (1987).
  • Biological activity appears dependent upon some form of proteolytic processing which results in the conversion of the precursor 31.5 kDa form to the mature 17.5 kDa form.
  • Evidence is growing that by inhibiting the conversion of precursor IL-1 ⁇ to mature IL-1 ⁇ , one can effectively inhibit the activity of interleukin-1.
  • Mammalian cells capable of producing IL-1 ⁇ include, but are not limited to, karatinocytes, endothelial cells, mesangial cells, thymic epithelial cells, dermal fibroblasts, chondrocytes, astrocytes, glioma cells, mononuclear phagocytes, granulocytes, T and B lymphocytes and NK cells.
  • interleukin-1 As discussed by J.J. Oppenheim, et al. Immunology Today, vol. 7(2):45-56 (1986), the activities of interleukin-1 are many. It has been observed that catabolin, a factor that promotes degradation of cartilage matrix, also exhibited the thymocyte comitogenic activities of IL-1 and stimulates chondrocytes to release collagenase neutral proteases and plasminogen activator.
  • proteolysis inducing factor stimulates muscle cells to produce prostaglandins which in turn leads to proteolysis, the release of amino acids and, in the long run, muscle wasting, and appears to represent a fragment of IL-1 with fever-inducing, acute phase response and thymocyte co-mitogenic activities.
  • IL-1 has multiple effects on cells involved in inflammation and wound healing.
  • Subcutaneous injection of IL-1 leads to margination of neutrophils and maximal extravascular infiltration of the polymorphonuclear leukocytes (PMN).
  • PMN polymorphonuclear leukocytes
  • Endothelial cells are stimulated to proliferate by IL-1 to produce thromboxane, to become more adhesive and to release procoagulant activity.
  • IL-1 also enhances collagen type IV production by epidermal cells, induces osteoblast proliferation and alkaline phosphatase production and stimulates osteoclasts to resorb bone.
  • macrophages have been reported to be chemotactically attracted to IL-1 to produce prostaglandins in response to IL-1 and to exhibit a more prolonged and active tumoricidal state.
  • IL-1 is also a potent bone resorptive agent capable upon infusion into mice of causing hypercaleemia and increas in bone resorptive surface as revealed by his to morphometry Sabatini, M. et al., PNAS 85: 5235-5239, 1988.
  • disease states in which the ICE inhibitors of Formula I may be useful as therapeutic agents include, but are not limited to, infectious diseases where active infection exists at any body site, such as meningitis and salpingitis; complications of infections including septic shock, disseminated intravascular coagulation, and/or adult respiratory distress syndrome; acute or chronic inflammation due to antigen, antibody, and/or complement deposition; inflammatory conditions including arthritis, cholangitis, colitis, encephalitis, endocarditis, glomerulonephritis, hepatitis, myocarditis, pancreatitis, pericarditis, reperfusion injury and vasculitis.
  • infectious diseases where active infection exists at any body site, such as meningitis and salpingitis
  • complications of infections including septic shock, disseminated intravascular coagulation, and/or adult respiratory distress syndrome; acute or chronic inflammation due to antigen, antibody, and/or complement deposition
  • inflammatory conditions including arthritis, cholangitis, colitis, ence
  • Immune-based diseases which may be responsive to ICE inhibitors of Formula I include but are not limited to conditions involving T-cells and/or macrophages such as acute and delayed hypersensitivity, graft rejection, and graft-versus-host-disease; auto-immune diseases including Type I diabetes mellitus and multiple sclerosis.
  • ICE inhibitors of Formula I may also be useful in the treatment of bone and cartilage resorption as well as diseases resulting in excessive deposition of extracellular matrix. Such diseases include periodonate diseases interstitial pulmonary fibrosis, cirrhosis, systemic sclerosis, and keloid formation.
  • ICE inhibitors of Formula I may also be useful in treatment of certain tumors which produce IL 1 as an autocrine growth factor and in preventing the cachexia associated with certain tumors.
  • Novel peptidyl aldehydes, ring chain tautomers and hydrates thereof of formula I are found to be potent inhibitors of interleukin-1 ⁇ converting enzyme (ICE).
  • ICE interleukin-1 ⁇ converting enzyme
  • Compounds of formula I are useful in the treatment of deseases including inflammation in lung, central nervous system, kidney, joints, endocardium, pericardium, eyes, ears, skin, gastrointestinal tract and urogenital system.
  • the invention encompasses compounds of formula I. or a pharmaceutically acceptable salt thereof thereof:
  • AA1, AA2 and AA3 are each independently selected from the group consisting of the L- and D- forms of the amino acids including glycine, alanine, valine, leucine, isoleucine, serine, threonine, aspartic acid, asparagine, glutamic acid, glutamine, lysine, hydroxy-lysine, histidine, arginine, phenylalanine, tyrosine, tryptophan, cysteine, methionine, ornithine, ⁇ -alanine, homoserine, homotyrosine, homophenylalanine and citrulline.
  • This invention also concerns to pharmaceutical composition and methods of treatment of interleukin-1 and interleukin-1 ⁇ mediated or implicated disorders or diseases (as described above) in a patient (including man and/or mammalian animals raised in the dairy, meat, or fur industries or as pets) in need of such treatment comprising administration of interleukin-1 ⁇ inhibitors of formula (I) as the active constituents.
  • this invention concerns pharmaceutical compositions and methods of treatment of diseases selected from septic shock, allograft rejection, inflammatory bowel disease and rheumatoid arthritis in a patient in need of such treatment comprising: administration of an interleukin-1 ⁇ inhibitor of formula (I) as the active constituent.
  • the alcohol II is then oxidized using dimethyl sulfoxide (DMSO), oxallyl chloride, and triethyl amine to the corresponding aldehyde which is protected as the dimethyl acetal using methanol, trimethyl orthoformate and p-toluenesulfonic acid to afford III.
  • DMSO dimethyl sulfoxide
  • oxallyl chloride oxallyl chloride
  • triethyl amine triethyl amine
  • the Alloc protecting group is then removed with tetrakis triphenylphosphine palladium in the presence of morpholine to afford amine IV.
  • N-CBZ-Aspartic acid ⁇ -methyl ester can be treated with i-butylchloroformate in the presence of N-methylmorpholine (NMM) followed by diazomethane to afford diazomethylketone XI.
  • NMM N-methylmorpholine
  • XII Treatment of XI with hydrochloric acid gives chloromethylketone XII, which can be used to alkylate the sodium salt of di-t-butyl malonate to give ketodiester XIII.
  • the t-butyl groups can be removed with trifluoro acetic acid and the resultant dicarboxylic acid can be decarboxylated in hot pyridine to afford keto acid XIV.
  • Acid XIV can then be coupled to benzyl amine using ethyldimethylaminopropyl carbodiimide in the presence of hydroxybenzotriazole (HOBt) to afford amide XV. Removal of the CBZ group is accomplished with hydrogen in the presence of 10% palladium on carbon to give amine XVI. This amine can then be coupled to N-acetyltyrosinyl-valinyl-alanine using dicyclohexyl carbodiimide in the presence of HOBt to afford XVII. Final deprotection of the carboxylic acid can be accomplished with lithium hydroxide to afford the desired ICE inhibitor XVIII.
  • HOBt hydroxybenzotriazole
  • N-Allyloxycarbonyl-3-amino-4-hydroxy-butanoic acid tert -butyl ester can be oxidized to the corresponding aldehyde using DMSO, oxalyl chloride and Hunig's base (Diisopropylethylamine).
  • the aldehyde is not isolated, but converted to the O-benzylacylal by treatment with benzyl alcohol and 3 ⁇ molecular sieves in the presence of a catalytic amount of p -toluene sulfonic acid followed by treatment with TFA (trifluoroacetic acid).
  • the alloc protecting group is removed in the presence of BOC-Val-Ala using tributyltin hydride and (PPh 3 ) 2 PdCl 2 . Coupling is then effected in the same flask using EDC and HOBt. The t -butoxycarbonyl protecting group is then removed with TFA and the resulting salt coupled to either 3-phenylpropionic acid or 3-(4-phydroxyphenyl)-propionic acid using EDC, HOBt and 4-methylmorpholine. The benzyl protecting group is then removed by hydrogenolysis using Pd(OH) 2 on carbon as a catalyst.
  • ketones shown in Scheme IV can be prepared as follows. 3-Allyloxycarbonylamino-4-hydroxy butanoic acid t-butyl ester can be oxidized using DMSO, oxallyl chloride, and either triethyl amine or Hunig's base to form the corresponding aldehyde. Grigniard reagents can then be added to the aldehyde to afford the secondary alcohol which can then be oxidized to the corresponding ketone using DMSO, oxallyl chloride, and triethyl amine, or pyridinium dichromate, or Dess-Martin periodinane. The alloc protecting group can then be removed with palladium(O) and tributyl tin hydride, and the resulting amine coupled to carboxylic acids EDC and HOBt. Treatment with TFA gives the desired inhibitors.
  • the hydroxy ketones shown in Scheme V can be prepared as follows. Enolization of 3-allyloxycarbonylamino-4-oxo-7-phenylheptanoic acid t-butyl ester with lithium hexamethyldisilazide can be followed by treatment with N-phenylsulphonyl oxaziridine to give the corresponding hydroxyketone. The alloc protecting group can then be removed with palladium(0) and tributyl tin hydride, and the resulting amine coupled to carboxylic acids using EDC and HOBt. Treatment with TFA gives the desired inhibitors.
  • the example shown in scheme VI can be prepared as follows. Phenylpropyl bromide is treated with magnesium to form the Grigniard reagent followed by di-t-Butyloxalate to afford the corresponding ⁇ -ketoester. Treatment of the ester with DAST (Diethylamino Sulphurtrifluoride) followed by deprotection with TFA and treatment with oxalyl chloride affords the desired acid chloride. Aspartic acid ⁇ -t-butyl ester is acylated with biphenylcarbonyl chloride followed by treatment with EDC to afford the desired oxazalone.
  • DAST Diethylamino Sulphurtrifluoride
  • TFA Trifluoride
  • oxalyl chloride affords the desired acid chloride.
  • Aspartic acid ⁇ -t-butyl ester is acylated with biphenylcarbonyl chloride followed by treatment with EDC to afford the desired oxazalone.
  • This invention also relates to a method of treatment for patients (including man and/or mammalian animals raised in the dairy, meat, or fur industries or as pets) suffering from disorders or diseases which can be attributed to IL-1/ICE as previously described, and more specifically, a method of treatment involving the administration of the IL-1/ICE inhibitors of formula (I) as the active constituents.
  • disease states in which the ICE inhibitors of Formula I may be useful as therapeutic agents include, but are not limited to, infectious diseases where active infection exists at any body site, such as meningitis and salpingitis; complications of infections including septic shock, disseminated intravascular coagulation, and/or adult respiratory distress syndrome; acute or chronic inflammation due to antigen, antibody, and/or complement deposition; inflammatory conditions including arthritis, cholangitis, colitis, encephalitis, endocarditis, glomerulonephritis, hepatitis, myocarditis, pancreatitis, pericarditis, reperfusion injury and vasculitis.
  • infectious diseases where active infection exists at any body site, such as meningitis and salpingitis
  • complications of infections including septic shock, disseminated intravascular coagulation, and/or adult respiratory distress syndrome; acute or chronic inflammation due to antigen, antibody, and/or complement deposition
  • inflammatory conditions including arthritis, cholangitis, colitis, ence
  • Immune-based diseases which may be responsive to ICE inhibitors of Formula I include but are not limited to conditions involving T-cells and/or macrophages such as acute and delayed hypersensitivity, graft rejection, and graft-versus-host-disease; auto-immune diseases including Type I diabetes mellitus and multiple sclerosis.
  • ICE inhibitors of Formula I may also be useful in the treatment of bone and cartilage resorption as well as diseases resulting in excessive deposition of extracellular matrix such as interstitial pulmonary fibrosis, cirrhosis, systemic sclerosis, and keloid formation.
  • ICE inhibitors of Formula I may also be useful in treatment of certain tumors which produce IL 1 as an autocrine growth factor and in preventing the cachexia associated with certain tumors.
  • the compounds of formula (I) may be administered orally, topically, parenterally, by inhalation spray or rectally in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles.
  • parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intracisternal injection or infusion techniques.
  • the compounds of the invention are effective in the treatment of humans.
  • compositions containing the active ingredient may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs.
  • Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets.
  • excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc.
  • the tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. They may also be coated by the techniques described in the U.S. Patents 4,256,108; 4,166,452; and 4,265,874 to form osmotic therapeutic tablets for control release.
  • Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin, or olive oil.
  • an inert solid diluent for example, calcium carbonate, calcium phosphate or kaolin
  • water or an oil medium for example peanut oil, liquid paraffin, or olive oil.
  • Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions.
  • excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyl-eneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorb
  • the aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl, p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.
  • preservatives for example ethyl, or n-propyl, p-hydroxybenzoate
  • coloring agents for example ethyl, or n-propyl, p-hydroxybenzoate
  • coloring agents for example ethyl, or n-propyl, p-hydroxybenzoate
  • flavoring agents for example ethyl, or n-propyl, p-hydroxybenzoate
  • sweetening agents such as sucrose or saccharin.
  • Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin.
  • the oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
  • Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives.
  • a dispersing or wetting agent e.g., glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerin, glycerin, glycerin, glycerin, glycerin, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerol
  • the pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions.
  • the oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these.
  • Suitable emulsifying agents may be naturally- occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate.
  • the emulsions may also contain sweetening and flavoring agents.
  • Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents.
  • the pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1,3-butane diol.
  • Suitable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid find use in the preparation of injectables.
  • the compounds of formula (I) may also be administered in the form of suppositories for rectal administration of the drug.
  • These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • Such materials are cocoa butter and polyethylene glycols.
  • creams, ointments, jellies, solutions or suspensions, etc., containing the compounds of Formula (I) are employed.
  • topical application shall include mouth washes and gargles.
  • Dosage levels of the order of from about 0.05 mg to about 140 mg per kilogram of body weight per day are useful in the treatment of the above- indicated conditions (about 2.5 mg to about 7 gms. per patient per day).
  • inflammation may be effectively treated by the administration of from about 0.01 to 50 mg of the compound per kilogram of body weight per day (about 0.5 mg to about 3.5 gms per patient per day).
  • the amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration.
  • a formulation intended for the oral administration of humans may contain from 0.5 mg to 5 gm of active agent compounded with an appropriate and convenient amount of carrier material which may vary from about 5 to about 95 percent of the total composition.
  • Dosage unit forms will generally contain between from about 1 mg to about 500 mg of an active ingredient.
  • the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination and the severity of the particular disease undergoing therapy.
  • N-allyloxycarbonyl-3-amino-4-hyroxybutanoic STEP A acid tert-butyl ester .
  • N-allyloxycarbonyl (S)-aspartic acid ⁇ -tert-butyl ester (2.00 g, 7.32 mmol) in 50 mL of tetrahydrofuran (THF) at 0°C, was added N-methyl morpholine (NMM, 885 mL, 8.05 mmol) followed by isobutyl chloroformate (IBCF, 997 mL, 7.68 mmol).
  • NMM N-methyl morpholine
  • IBCF isobutyl chloroformate
  • N-allyloxycarbonyl-3-amino-4-oxobutanoic STEP B acid ⁇ -tert-butyl ester dimethyl acetal .
  • oxalyl chloride 508 mL, 5.82 mmol.
  • N-allyloxycarbonyl-3-amino-4-hyroxybutanoic acid tert-butyl ester 1.25 g, 4.85 mmol
  • N-(N-Acetyl-tyrosinyl-valinyl-alaninyl)-3-amino-4-oxobutanoic acid ⁇ -tert-butyl ester dimethyl acetal To a solution of 3-Amino-4-oxobutanoic acid ⁇ -tert-butyl ester dimethyl acetal (104 mg, 0.473 mmol) in 3 mL of DMF at 0°C was added N-methyl morpholine (260 mL, 2.37 mmol) followed sequentially by N-Acetyl-tyrosinyl-valinyl-alanine (229 mg, 0.473 mmol), hydroxybenzotriazole (96 mg, 0.710 mmol), and dicyclohexylcarbodiimide (98 mg, 0.473 mmol).
  • N-(N-Acetyl-tyrosinyl-valinyl-alaninyl)-3-amino-4-oxobutanoic STEP E acid A solution of N-(N-Acetyl-tyrosinyl-valinyl-alaninyl)-3-amino-4-oxobutanoic acid ⁇ -tert-butyl ester dimethyl acetal (17.4 mg) in 2 mL of trifluoroacetic acid was aged for 15 minutes and concentrated in vacuo . The product was dissolved in 1.0 mL of methanol and 1.0 mL of water containing 60 uL of thionyl chloride was added.
  • N-(N-Acetyl-tyrosinyl-valinyl- ⁇ -CBZ-lysinyl)-3-amino-4-oxobutanoic acid A solution of N-(N-Acetyl-tyrosinyl-valinyl- ⁇ -CBZ-lysinyl)-3-amino-4-oxobutanoic acid ⁇ -tert-butyl ester dimethyl acetal (14.9 mg) was treated with 1 mL of trifluoroacetic acid, aged for 15 minutes, and concentrated in vacuo . The residue was dissolved in 1.0 mL of methanol and 1.0 mL of water containing 20 uL of thionyl chloride was added.
  • N-(N-Acetyl-tyrosinyl-valinyl-lysinyl)-3-amino-4-oxobutanoic acid A solution of N-(N-Acetyltyrosinyl-valinyl- ⁇ -CBZ-lysinyl)-3-amino-4-oxobutanoic acid ⁇ -tert-butyl ester dimethyl acetal (16.8 mg) was dissolved in 2 mL of methanol and 10 mg of Pearlman's catalyst (Pd(OH) 2 on Carbon) was added. After 30 minutes under hydrogen, the mixture was filtered and concentrated.
  • Pearlman's catalyst Pd(OH) 2 on Carbon
  • N-(N-Acetyl-tyrosinyl-valinyl-lysinyl)-3-amino-4-oxobutanoic acid dimethyl acetal lithium salt A solution of N-(N-Acetyl-tyrosinyl-valinyl- ⁇ -CBZ-lysinyl)-3-amino-4-oxobutanoic acid ⁇ -tert-butyl ester dimethyl acetal (15.6 mg) was disolved in 2 mL of methanol and 10 mg of Pearlman's catalyst (Pd(OH) 2 on Carbon) was added. After 30 min under hydrogen, the mixture was filtered and concentrated.
  • Pearlman's catalyst Pd(OH) 2 on Carbon
  • the mixture was diluted with ethyl acetate and washed with water, 1 N sodium hydrogen sulfate, and three times with water. The organics were dried over sodium sulfate, filtered, and concentrated.
  • the resulting colorless oil was dissolved in 7 mL of dichloromethane and 6.5 mL of benzyl alcohol. To this solution was added ⁇ 1g of 3 ⁇ molecular sieves followed by a catalytic amount of p -toluenesulfonic acid. After 16 hours, trifluoroacetic acid ( ⁇ 8 mL) was added, and the mixture stirred for 30 minutes and concentrated. The mixture was diluted with ethyl acetate and filtered through CELITE.
  • N-( Tert -butoxycarbonyl-valinyl-alaninyl)-4-amino-5-benzyloxy-2-oxotetrahydrofuran (590.4 mg) was dissolved in 15 mL of trifluoroacetic acid, aged for 15 minutes, and concentrated. The residue was dissolved in methanol, diluted with toluene and concentrated to give a colorless solid. To 202.6 mg of this solid was added 3-(4-hydroxyphenyl)-propionic acid (137 mg, 0.8245 mmol), hydroxybenzotriazole (111 mg, 0.8245 mmol), dimethyl formamide (3 mL), and 4-methylmorpholine (45 ⁇ L, 0.4122 mmol).
  • Ethyl dimethylaminopropyl carbodiimide (83 mg, 0.433 mmol) was added and the mixture stirred for 16 hours at ambient temperature. The mixture was diluted with ethyl acetate and washed three times with 2 N hydrochloric acid, and twice with dilute sodium bicarbonate.
  • N-( Tert -butoxycarbonyl-valinyl-alaninyl)-4-amino-5-benzyloxy-2-oxotetrahydrofuran (590.4 mg) was dissolved in 15 mL of trifluoroacetic acid, aged for 15 minutes, and concentrated. The residue was dissolved in methanol, diluted with toluene and concentrated to give a colorless solid. To 201.9 mg of this solid was added 3-phenylpropionic acid (123 mg, 0.8216 mmol), hydroxybenzotriazole (111 mg, 0.8216 mmol), dimethyl formamide (3 mL), and 4-methylmorpholine (45 ⁇ l, 0.4108 mmol).
  • Ethyl dimethylaminopropyl carbodiimide (83 mg, 0.4313 mmol) was added and the mixture stirred for 16 hours at ambient temperature. The mixture was diluted with ethyl acetate and washed three times with 2 N hydrochloric acid, and twice with dilute sodium bicarbonate.
  • N-(3-Phenylpropionyl-Valinyl-Alaninyl)3-amino-4-oxo-5-phenylpentanoic acid 3-Allyloxycarbonylamino-4-oxo-5-phenylpentanoic acid t-butyl ester (25 mg, 0.0717 mmol) was dissolved in CH 2 Cl 2 (2 mL). PdCl 2 (Ph 3 P) 2 (cat.) and Bu 3 SnH (30 ⁇ l)was added dropwise. The mixture was stirred for under N 2 for 10 min.
  • N-(3-Phenylpropionyl-Valinyl-Alaninyl)3-amino-4-oxo-6-phenylhexanoic acid 3-Allyloxycarbonylamino-4-oxo-6-phenylhexanoic acid t-butyl ester (170 mg, 0.472 mmol) was dissolved in CH 2 Cl 2 (6 mL). PdCl 2 (Ph 3 P) 2 (cat.) and Bu 3 SnH (0.194 ml)was added dropwise the mixture was stirred for under N 2 for 10 min.
  • N-(3-Phenylpropionyl-Valinyl-Alaninyl)3-amino-4-oxo-7-phenylheptanoic acid 3-Allyloxycarbonylamino-4-oxo-7-phenylheptanoic acid t-butyl ester (300 mg, .81 mmol) was dissolved in CH 2 Cl 2 (10 mL). PdCl 2 (Ph 3 P) 2 (cat.) and Bu 3 SnH (0.331 mmol) ml) was added dropwise. The mixture was stirred for under N 2 for 10 min.
  • N-(N-AcetylTyrosinyl-Valinyl-Alaninyl)-3-amino-4-hydroxy-7-phenyl heptanoic acid t-butyl ester 3-Allyloxycarbonylamino-4-oxo-7-phenylheptanoic acid t-butyl ester (155 mg, .41 mmol) was dissolved in CH 2 Cl 2 (4 mL). PdCl 2 (Ph 3 P) 2 (cat.) and Bu 3 SnH (0.14 mL) was added dropwise. The mixture was stirred for under N 2 for 10 min.
  • N-(N-AcetylTyrosinyl-Valinyl-Alaninyl)-3-amino-4-oxo-7-phenyl heptanoic acid t-butyl ester N-(N-Acetyl-Tyrosinyl-Valinyl-Alaninyl)-3-amino-4-hydroxy-7-phenyl heptanoic acid t-butyl ester (166 mg, 0.0991 mmol), was dissolved in CH 2 Cl 2 (5 mL) and PDC (56 mg, 0.149 mmoL), was added. The resulting mixture was stirred at rt for 6h. The mixture was filtered through Celite and the solvent was concentrated in vacuo.
  • N-(N-AcetylTyrosinyl-Valinyl-Alaninyl)-3-amino-4-oxo-7 - phenyl heptanoic acid N-(N-AcetylTyrosinyl-Valinyl-Alaninyl)-3-amino-4-oxo-7-phenyl hepttanoic acid t-butyl ester (12 mg) was stirred with MeOH (0.5 mL), water(.2 mL), and 2N NaOH (0.1 mL) overnight. The mixture was acidified with 2N HCl and was extracted with EtOAc (3X5 mL).
  • N-(N-AcetylTyrosinyl-Valinyl-Alaninyl)-3-amino-4-oxo-8-phenyl octanoic acid t-butyl ester 3-Allyloxycarbonyl-amino-4-oxo-8-phenyloctanoic acid t-butyl ester (100 mg, .26 mmol) was dissolved in CH 2 Cl 2 (2 mL). PdCl 2 (Ph 3 P) 2 (cat.) and Bu 3 SnH (0.107 mL) was added dropwise. The mixture was stirred for under N 2 for 10 min.
  • N-(N-AcetylTyrosinyl-Valinyl-Alaninyl)-3-amino-4-oxo-8-phenyl octanoic acid N-(N-AcetylTyrosinyl-Valinyl-Alaninyl Alaninyl)-3-amino-4-oxo-8-phenyl octanoic acid t-butyl ester (100 mg) was dissolved in a 1:1 mixture of CH 2 Cl 2 /TFA (10 mL). The mixture was stirred at rt for 30 min and the solvent was reduced in vacuo.
  • N-(N-AcetylTyrosinyl-Valinyl-Alaninyl)-3-amino-4-oxo-9-phenyl nonanoic acid t-butyl ester 3-Allyloxycarbonylamino-4-hydroxy-9-phenylnonanoic acid t-butyl ester (360 mg, 0.9.5 mmol) was dissolved in CH 2 Cl 2 (5 mL) and Dess-Martin reagent (576 mg, 1.35 mmol) was added.
  • N-(N-AcetylTyrosinyl-Valinyl-Alaninyl)-3-amino-4-oxo-9-phenyl nonanoic acid N-(N-AcetylTyrosinyl-Valinyl-Alaninyl)-3-amino-4-oxo-9-phenyl nonanoic acid t-butyl ester (140 mg) was dissolved in a 1:1 mixture of CH 2 Cl 2 /TFA (8 mL). The mixture was stirred at rt for 30 min and the solvent was reduced in vacuo. The residue was recrystilized from acetone/hexane to provide the acid (120 mg, 80%).
  • N-(N-AcetylTyrosinyl-Valinyl-Alaninyl)-3-amino-5-hydroxy-4-oxo-7-phenyl heptanoic acid t-butyl ester 3-Allyloxycarbonylamino-5-hydroxy-4-oxo-7-phenylheptanoic acid t-butyl ester (62 mg, .64 mmol) was dissolved in CH 2 Cl 2 (3 mL). PdCl 2 (Ph 3 P) 2 (cat.) and Bu 3 SnH (0.067 mL) was added dropwise. The mixture was stirred under N 2 for 10 min.
  • N-(N-AcetylTyrosinyl-Valinyl-Alaninyl)-3-amino-5-hydroxy-4-oxo-7-phenyl heptanoic acid N-(N-AcetylTyrosinyl-Valinyl-Alaninyl)-3-amino-5-hydroxy-4-oxo-7-phenyl heptanoic acid t-butyl ester (40 mg) was dissolved in a 1:1 mixture of CH 2 Cl 2 /TFA (6 mL). The mixture was stirred at room temperature for 30 min and the solvent was reduced in vacuo. The residue was recrystilized from acetone/hexane to provide the acid (33 mg).
  • phenylpropyl bromide(7.64mL, 50.23mmo l ) was added to a suspension of magnesium turning (1.22g,50.23mmol) in ether(20mL) maintaining gentle reflux. The resulting mixture was stirred for additional 1h and was added slowly over 30min. to di-t-butyloxalate(10.16g,50.23mmol) dissolved in CH 2 Cl 2 (200mL) at -78°C.
  • t-Butyl(5-phenyl-2,2-difluoro) pentanoate t-Butyl(5-phenyl-2,2-difluoro) pentanoate.: t-Butyl-5-phenyl-2-oxo-pentanoate(9g) was dissolved in CH 2 Cl 2 (140mL) and dimethylaminofulfur triflouride (8.45mL) was added dropwise at 0°C. The resulting mixture was stirred at rt for 18h. the reaction mixture was cooled to 0°C and quinched with 1N aq NH 4 Cl. The mixture was extracted with ether (3X150mL). The combined organic extracts was dried over Na 2 SO 4 .
  • 5-Phenyl-2,2-difluoro-pentanoicacid chloride To the 5-phenyl-2,2-difluoro-pentanoic acid (1.5g,7mmol) in CH 2 Cl 2 (3mL) was added 2M oxalyl chloride(4.2mL, 8.4mmol) in CH 2 Cl 2 and DMF(cat.). The resulting mixture was stirred at rt for 1h. the solvent was evaporated and the residue was distilled (70-75°C, 0.1mmHg) to provide the acid chloride (1.25g).
  • N-(4-Bi-phenylcarbonyl) b-t-butyl- Aspartic acid to aspartic acid (6.)g) in dry THF (100mL) was added 4-bi-phenylcarbonyl cholride (3.44g). the resulting mixture was stirred for 17h. water (3001LO) was added and the mixture was extracted with EtOAc(3X100mL). The combined organic extracts was dried over Na2SO4 and the solvent was evaporated to provide the title compound (3.8g).
  • N-(3-Phenylpropionyl-Valinyl-Alaninyl) 3-amino -4-hydroxy-5,5-difluoro-8-phenyl t-butyloctanoate To 3-(4-Bi-phenylcarbonylamino)-4-hydroxy-5,5-difluoro-8-ph enyloctanoic acid t-butylester(252mg,0.5mmol) in MeOH(5mL) was added 3% Na-Hg(4mmol, 8eq) and NaHh 2 PO 4 (6mmol, 12eq). The mixture was stirred at rt for 1h and filtered into 1N aq HCl(8eq).
  • N-(3-Phenylpropionyl-Valinyl-Alaninyl) 3-amino -4-oxo-5,5-difluoro-8-phenyl t-butyloctanoate To N-(3-Phenylpropionyl-Valinyl-Alaninyl) 3-amino -4-hydroxy-5,5-difluoro-7-phenyl t-butylheptanoate (150mg) in CH 2 Cl 2(5mL) was added Dess-Martin reagent (750mg). The mixture was stirred for 5h and filtered. The solvent was evaporated and the residue was chromatographed over silica (95:5, CH 2 Cl 2 :MeOH) to provide the title compound(130mg)
  • N-(3-Phenylpropionyl-Valinyl-Alaninyl) 3-amino -4-oxo-5,5-difluoro-7-phenyl t-butylheptanoate(130mg) was dissolved in a 1:1 mixture of CH 2 Cl 2 /TFAA(6ml) and stirred for 1h. The solvent was evaporated to provide the title compound(110mg).

Claims (7)

  1. Eine Verbindung der Formel I
    Figure 00910001
    oder ein pharmazeutisch annehmbares Salz davon, worin Y
    Figure 00910002
    ist;
    worin:
    R1 ist
    (a) substituiertes C1-6-Alkyl, worin der Substituent ausgewählt ist aus
    (1) Wasserstoff,
    (2) Hydroxy und
    (3) Chlor oder Fluor,
    (b) Aryl-C1-6-alkyl, worin die Arylgruppe ausgewählt ist aus der Gruppe, bestehend aus
    (1) Phenyl,
    (2) Naphthyl,
    (3) Pyridyl,
    (4) Furyl,
    (5) Thienyl,
    (6) Thiazolyl,
    (7) Isothiazolyl,
    (8) Benzofuryl,
    (9) Benzothienyl,
    (10) Indolyl,
    (11) Isooxazolyl und
    (12) Oxazolyl,
    und mono- und disubstituiertem C6-10-Aryl, wie es oben in den Punkten (1) bis (12) definiert ist, wobei die Substituenten unabhängig voneinander C1-4-Alkyl, Halogen oder Hydroxy sind;
    R2H oder Deuterium ist;
    AA1 ausgewählt ist aus der Gruppe, bestehend aus
    (a) einer Einfachbindung und
    (b) einer Aminosäure der Formel AI
    Figure 00920001
    worin
    R7 ausgewählt ist aus der Gruppe, bestehend aus
    (a) Wasserstoff,
    (b) substituiertem C1-6-Alkyl, wobei der Substituent ausgewählt ist aus
    (1) Wasserstoff,
    (2) Hydroxy,
    (3) Halogen,
    (4) -S-C1-4-Alkyl,
    (5) -SH,
    (6) C1-6-Alkylcarbonyl,
    (7) Carboxy,
    (8)
    Figure 00920002
    (9) C1-4-Alkylamino und C1-4-Alkylamino, worin der Alkylrest mit einer Hydroxygruppe substituiert ist, und
    (10) Guanidino, und
    (c) Aryl-C1-6-alkyl, worin die Arylgruppe wie oben in diesem Anspruch definiert ist, wobei das Aryl gegebenenfalls mono- oder disubstituiert ist und die Substituenten jeweils unabhängig voneinander C1-6-Alkyl, Halogen, Hydroxy, C1-6-Alkylamino, C1-6-Alkoxy, C1-6-Alkylthio oder C1-6-Alkylcarbonyl sind;
    AA2 ausgewählt ist aus der Gruppe, bestehend aus
    (a) einer Einfachbindung und
    (b) einer Aminosäure der Formel AII
    Figure 00930001
    worin R8 ausgewählt ist aus der Gruppe, bestehend aus
    (a) Wasserstoff,
    (b) substituiertem C1-6-Alkyl, wobei der Substituent ausgewählt ist aus
    (1) Wasserstoff,
    (2) Hydroxy,
    (3) Halogen,
    (4) -S-C1-4-Alkyl,
    (5) -SH,
    (6) C1-6-Alkylcarbonyl,
    (7) Carboxy,
    (8)
    Figure 00930002
    (9) C1-4-Alkylamino und C1-4-Alkylamino, worin der Alkylrest mit einer Hydroxygruppe substituiert ist, und
    (10) Guanidino, und
    (c) Aryl-C1-6-alkyl,
    worin Aryl wie oben in diesem Anspruch definiert ist, wobei das Aryl gegebenenfalls mono- oder disubstituiert ist und die Substituenten jeweils unabhängig voneinander C1-6-Alkyl, Halogen, Hydroxy, C1-6-Alkylamino, C1-6-Alkoxy, C1-6-Alkylthio oder C1-6-Alkylcarbonyl sind.
  2. Eine Verbindung gemäß Anspruch 1, worin
    AA3 ausgewählt ist aus der Gruppe, bestehend aus
    (a) einer Einfachbindung und
    (b) einer Aminosäure der Formel AIII
    Figure 00940001
    R9 ausgewählt ist aus der Gruppe, bestehend aus
    (a) Wasserstoff,
    (b) substituiertem C1-6-Alkyl, wobei der Substituent ausgewählt ist aus
    (1) Wasserstoff,
    (2) Hydroxy,
    (3) Halogen,
    (4) -S-C1-4-Alkyl,
    (5) -SH,
    (6) C1-6-Alkylcarbonyl,
    (7) Carboxy,
    (8)
    Figure 00940002
    (9) C1-4-Alkylamino und C1-4-Alkylamino, worin der Alkylrest mit einer Hydroxygruppe substituiert ist,
    oder
    (10) Guanidino, und
    (c) Aryl-C1-6-alkyl, worin Aryl ausgewählt ist aus der Gruppe, bestehend aus
    (1) Phenyl,
    (2) Naphthyl,
    (3) Pyridyl,
    (4) Furyl,
    (5) Thienyl,
    (6) Thiazolyl,
    (7) Isothiazolyl,
    (8) Benzofuryl,
    (9) Benzothienyl,
    (10) Indolyl,
    (11) Isooxazolyl und
    (12) Oxazolyl,
    wobei die Arylgruppe gegebenenfalls mono- oder disubstituiert ist und die Substituenten jeweils unabhängig voneinander C1-6-Alkyl, Halogen, Hydroxy, C1-6-Alkylamino, C1-6-Alkoxy, C1-6-Alkylthio oder C1-6-Alkylcarbonyl sind.
  3. Eine Verbindung gemäß Anspruch 2, worin AA2 eine Aminosäure der Formel AII ist
    Figure 00950001
    worin
    R8 ausgewählt ist aus der Gruppe, bestehend aus
    (a) Wasserstoff,
    (b) substituiertem C1-6-Alkyl, wobei der Substituent ausgewählt ist aus
    (1) Wasserstoff,
    (2) Hydroxy,
    (3) Halogen,
    (4) -S-C1-4-Alkyl,
    (5) -SH,
    (6) C1-6-Alkylcarbonyl,
    (7) Carboxy,
    (8)
    Figure 00960001
    (9) C1-4-Alkylamino und C1-4-Alkylamino, worin der Alkylrest mit einer Hydroxygruppe substituiert ist, und
    (10) Guanidino, und
    (c) Aryl-C1-6-alkyl,
    worin Aryl ausgewählt ist aus der Gruppe, bestehend aus
    (1) Phenyl,
    (2) Naphthyl,
    (3) Pyridyl,
    (4) Furyl,
    (5) Thienyl,
    (6) Thiazolyl,
    (7) Isothiazolyl,
    (8) Benzofuryl,
    (9) Benzothienyl,
    (10) Indolyl,
    (11) Isooxazolyl und
    (12) Oxazolyl,
    wobei die Arylgruppe gegebenenfalls mono- oder disubstituiert ist und die Substituenten jeweils unabhängig voneinander C1-6-Alkyl, Halogen, Hydroxy, C1-6-Alkylamino, C1-6-Alkoxy, C1-6-Alkylthio oder C1-6-Alkylcarbonyl sind; und
    AA3 eine Aminosäure der Formel AIII ist
    Figure 00960002
    worin
    R9 ausgewählt ist aus der Gruppe, bestehend aus
    (a) Wasserstoff,
    (b) substituiertem C1-6-Alkyl, wobei der Substituent ausgewählt ist aus
    (1) Wasserstoff,
    (2) Hydroxy,
    (3) Halogen,
    (4) -S-C1-4-Alkyl,
    (5) -SH,
    (6) C1-6-Alkylcarbonyl,
    (7) Carboxy,
    (8)
    Figure 00970001
    (9) C1-4-Alkylamino und C1-4-Alkylamino, worin der Alkylrest mit einer Hydroxygruppe substituiert ist, und
    (10) Guanidino, und
    (c) Aryl-C1-6-alkyl,
    worin Aryl wie oben in diesem Anspruch definiert ist und die Arylgruppe gegebenenfalls mono- oder disubstituiert ist und die Substituenten jeweils unabhängig voneinander C1-6-Alkyl, Halogen, Hydroxy, C1-6-Alkylamino, C1-6-Alkoxy, C1-6-Alkylthio oder C1-6-Alkylcarbonyl sind.
  4. Eine Verbindung gemäß Anspruch 3, worin R1 C1-3-Alkyl oder Aryl-C1-6-alkyl ist, wobei Aryl Phenyl, Naphthyl, Thienyl oder Benzothienyl ist;
    worin
    R7 C1-6-Alkyl oder Aryl-C1-6-alkyl ist, wobei Aryl definiert ist als
    (1) Phenyl,
    (2) Naphthyl,
    (3) Pyridyl,
    (4) Furyl,
    (5) Thienyl,
    (6) Thiazolyl,
    (7) Isothiazolyl,
    (8) Benzofuryl,
    (9) Benzothienyl,
    (10) Indolyl,
    (11) Isooxazolyl und
    (12) Oxazolyl,
    und worin die Arylgruppe der Punkte (1) bis (12) gegebenenfalls mono- oder disubstituiert ist und die Substituenten jeweils unabhängig voneinander C1-6-Alkyl, Halogen, Hydroxy, C1-6-Alkylamino, C1-6-Alkoxy, C1-6-Alkylthio oder C1-6-Alkylcarbonyl sind;
    R8 und R9 jeweils unabhängig voneinander sind
    (a) Wasserstoff,
    (b) C1-6-Alkyl,
    (c) Mercapto-C1-6-alkyl,
    (d) Hydroxy-C1-6-alkyl,
    (e) carboxy-C1-6-alkyl,
    (g) Aminocarbonyl-C1-6-alkyl,
    (h) Mono- oder Di-C1-6-alkylamino-C1-6-alkyl,
    (i) Guanidino-C1-6-alkyl,
    (j) Amino-C1-6-alkyl oder N-substituiertes Amino-C1-6-alkyl, wobei der Substituent Carbobenzoxy ist, oder
    (k) Aryl-C1-6-alkyl, worin die Arylgruppe ausgewählt ist aus Phenyl und Indolyl und die Arylgruppe mit Wasserstoff, Hydroxy oder C1-3-Alkyl monosubstituiert ist.
  5. Eine Verbindung gemäß Anspruch 3, worin R1 C1-3-Alkyl oder Aryl-C1-6-alkyl ist, wobei Aryl Phenyl, Naphthyl, Thienyl oder Benzothienyl ist;
    R2
    Figure 00980001
    ist,
    worin
    R4 und R5 jeweils unabhängig voneinander ausgewählt sind aus Wasserstoff, Hydroxy oder Fluor;
    R6 Aryl-C1-6-alkyl ist, worin die Alkylgruppe mit Wasserstoff, Oxo, C1-3-Alkyl, Halogen oder Hydroxy substituiert ist,
    wobei Aryl ausgewählt ist aus der Gruppe, bestehend aus
    (1) Phenyl,
    (2) Naphthyl,
    (3) Pyridyl,
    (4) Furyl,
    (5) Thienyl,
    (6) Thiazolyl,
    (7) Isothiazolyl,
    (8) Benzofuryl,
    (9) Benzothienyl,
    (10) Indolyl,
    (11) Isooxazolyl und
    (12) Oxazolyl,
    wobei die Arylgruppe gegebenenfalls mono- oder disubstituiert ist und die Substituenten jeweils unabhängig voneinander C1-3-Alkyl, Halogen, Hydroxy, C1-3-Alkylamino, C1-3-Alkoxy, C1-3-Alkylthio oder C1-3-Alkylcarbonyl sind;
    R7 C1-6-Alkyl oder Aryl-C1-6-alkyl ist, worin Aryl wie oben in diesem Anspruch definiert ist und worin die Arylgruppe gegebenenfalls mono- oder disubstituiert ist und die Substituenten jeweils unabhängig voneinander C1-6-Alkyl, Halogen, Hydroxy, C1-6-Alkylamino, C1-6-Alkoxy, C1-6-Alkylthio oder C1-6-Alkylcarbonyl sind.
  6. Eine Verbindung gemäß Anspruch 4 oder 5, worin:
    R1 Methyl oder Phenyl-C1-6-alkyl oder Hydroxyphenyl-C1-6-alkyl ist; AA1 eine Einfachbindung oder eine Aminosäure der Formel AI ist
    Figure 00990001
    worin
    R7
    (a) C1-6-Alkyl,
    (b) substituiertes Phenyl-C1-3-alkyl, worin der Substituent Wasserstoff, Hydroxy, Carboxy oder C1-4-Alkyl ist, oder
    (c) Indolylmethyl ist;
    R8 C1-6-Alkyl ist; und
    R9
    (a) Wasserstoff,
    (b) C1-6-Alkyl,
    (c) Amino-C1-4-alkyl,
    (d) N-Carbobenzoxyamino(n-butyl),
    (e) Carbamylmethyl,
    (f) Indol-2-ylmethyl oder
    (g) substituiertes Phenyl-C1-3-alkyl ist, wobei der Substituent Wasserstoff, Hydroxy, Carboxy oder C1-4-Alkyl ist.
  7. Eine Verbindung gemäß Anspruch 6, worin
    R6 Phenyl-C1-6-alkyl ist, worin die Alkylgruppe mit Wasserstoff, Oxo, C1-3-Alkyl, Halogen oder Hydroxy substituiert ist, und worin die Phenylgruppe mono- oder disubstituiert sein kann und die Substituenten jeweils unabhängig voneinander C1-3-Alkyl, Halogen, Hydroxy, C1-3-Alkylamino, C1-3-Alkoxy, C1-3-Alkylthio oder C1-3-Alkylcarbonyl sind;
    R9
    (a) Wasserstoff,
    (b) C1-6-Alkyl,
    (c) Amino-C1-4-alkyl,
    (d) N-Carbobenzoxyamino(n-butyl),
    (e) Carbamylmethyl,
    (f) Indol-2-ylmethyl oder
    (g) substituiertes Phenyl-C1-3-alkyl ist, wobei der Substituent Wasserstoff oder Hydroxy ist.
EP92305670A 1991-06-21 1992-06-19 Peptidylderivate als Inhibitoren von Interleukin-1B-konvertierenden Enzymen Expired - Lifetime EP0519748B1 (de)

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
US71889291A 1991-06-21 1991-06-21
US718892 1991-06-21
US81115791A 1991-12-19 1991-12-19
US88955592A 1992-05-27 1992-05-27
US889555 1992-05-27
US811157 2004-03-29

Publications (3)

Publication Number Publication Date
EP0519748A2 EP0519748A2 (de) 1992-12-23
EP0519748A3 EP0519748A3 (en) 1993-05-05
EP0519748B1 true EP0519748B1 (de) 1998-09-02

Family

ID=27418985

Family Applications (1)

Application Number Title Priority Date Filing Date
EP92305670A Expired - Lifetime EP0519748B1 (de) 1991-06-21 1992-06-19 Peptidylderivate als Inhibitoren von Interleukin-1B-konvertierenden Enzymen

Country Status (5)

Country Link
US (1) US5434248A (de)
EP (1) EP0519748B1 (de)
JP (1) JPH06102642B2 (de)
CA (1) CA2071674C (de)
DE (1) DE69226820T2 (de)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7034043B2 (en) 1999-08-13 2006-04-25 Biogen Idec Ma Inc. Cell adhesion inhibitors
US7196112B2 (en) 2004-07-16 2007-03-27 Biogen Idec Ma Inc. Cell adhesion inhibitors
US7417029B2 (en) 2000-05-19 2008-08-26 Vertex Pharmaceuticals Incorporated Prodrug of an ice inhibitor

Families Citing this family (59)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6008217A (en) * 1995-12-20 1999-12-28 Vertex Pharmaceuticals Incorporated Inhibitors of interleukin-1β converting enzyme
US6204261B1 (en) 1995-12-20 2001-03-20 Vertex Pharmaceuticals Incorporated Inhibitors of interleukin-1β Converting enzyme inhibitors
US5874424A (en) * 1995-12-20 1999-02-23 Vertex Pharmaceuticals Incorporated Inhibitors of interleukin-1β converting enzyme
JPH08500482A (ja) * 1992-06-12 1996-01-23 マサチューセッツ インスティテュート オブ テクノロジー Ｃｅｄ−３及び関連蛋白質のインヒビター
US5985838A (en) 1993-04-29 1999-11-16 Vertex Pharmaceuticals, Inc. Peptide analogs as irreversible interleukin-1β protease inhibitors
US5462939A (en) * 1993-05-07 1995-10-31 Sterling Winthrop Inc. Peptidic ketones as interleukin-1β-converting enzyme inhibitors
JPH0789951A (ja) * 1993-06-03 1995-04-04 Sterling Winthrop Inc インターロイキン−１β転換酵素阻害剤
US5843905A (en) * 1993-06-04 1998-12-01 Vertex Pharmaceuticals, Incorporated Peptidic phosphinyloxymethyl ketones as interleukin-1β-converting enzyme inhibitors
DK0628550T3 (da) 1993-06-08 1998-09-28 Vertex Pharma Pyridazin som interleukin-1 beta-omdannede enzyminhibitorer
US5594106A (en) * 1993-08-23 1997-01-14 Immunex Corporation Inhibitors of TNF-α secretion
NO943210L (no) * 1993-09-03 1995-03-06 Takeda Chemical Industries Ltd Laktolderivater, deres fremstilling og anvendelse
US5798247A (en) * 1994-05-06 1998-08-25 Basf Aktiengesellschaft Organic-chemical compound with ice-inhibitory action
US5552400A (en) * 1994-06-08 1996-09-03 Sterling Winthrop Inc. Fused-bicyclic lactams as interleukin-1β converting enzyme inhibitors
US5847135A (en) * 1994-06-17 1998-12-08 Vertex Pharmaceuticals, Incorporated Inhibitors of interleukin-1β converting enzyme
US6420522B1 (en) 1995-06-05 2002-07-16 Vertex Pharmaceuticals Incorporated Inhibitors of interleukin-1β converting enzyme
US5716929A (en) * 1994-06-17 1998-02-10 Vertex Pharmaceuticals, Inc. Inhibitors of interleukin-1β converting enzyme
US5756466A (en) * 1994-06-17 1998-05-26 Vertex Pharmaceuticals, Inc. Inhibitors of interleukin-1β converting enzyme
US5565430A (en) * 1994-08-02 1996-10-15 Sterling Winthrop Inc. Azaaspartic acid analogs as interleukin-1β converting enzyme inhibitors
US7001921B1 (en) 1995-01-23 2006-02-21 Biogen Idec Ma Inc. Cell adhesion inhibitors
US6306840B1 (en) * 1995-01-23 2001-10-23 Biogen, Inc. Cell adhesion inhibitors
CA2215211A1 (en) * 1995-03-31 1996-10-03 Takeda Chemical Industries, Ltd. Cysteine protease inhibitor
US5798442A (en) * 1995-04-21 1998-08-25 Merck Frosst Canada, Inc. Peptidyl derivatives as inhibitors of pro-apoptotic cysteine proteinases
US6248713B1 (en) 1995-07-11 2001-06-19 Biogen, Inc. Cell adhesion inhibitors
EP0761680A3 (de) * 1995-09-12 1999-05-06 Ono Pharmaceutical Co., Ltd. Tetrazolverbindungen mit Interleukin-1beta-konvertierendes Enzym inhibierende Aktivität
US5843904A (en) * 1995-12-20 1998-12-01 Vertex Pharmaceuticals, Inc. Inhibitors of interleukin-1βconverting enzyme
US6136834A (en) * 1995-12-27 2000-10-24 Ono Pharmaceutical Co., Ltd. Tetrazole compounds and pharmaceutical agents containing such derivative
US6288037B1 (en) 1996-01-29 2001-09-11 Basf Aktiengesellschaft Substrates and inhibitors for cysteine protease ICH-1
WO1997034473A1 (en) * 1996-03-21 1997-09-25 The Trustees Of Columbia University In The City Of New York Craf1 (traf-3) isoforms and uses thereof
US6239108B1 (en) 1996-07-11 2001-05-29 Biogen, Inc. Cell adhesion inhibitors
US6686350B1 (en) 1996-07-25 2004-02-03 Biogen, Inc. Cell adhesion inhibitors
CA2261974A1 (en) 1996-07-25 1998-02-05 Biogen, Inc. Molecular model for vla-4 inhibitors
US5869519A (en) * 1996-12-16 1999-02-09 Idun Pharmaceuticals, Inc. C-terminal modified (n-substituted)-2-indolyl dipeptides as inhibitors of the ICE/ced-3 family of cysteine proteases
US5968927A (en) 1996-09-20 1999-10-19 Idun Pharmaceuticals, Inc. Tricyclic compounds for the inhibition of the ICE/ced-3 protease family of enzymes
NZ334906A (en) 1996-10-11 2000-09-29 Basf Ag A sulphonamido pentanoic acid derivative useful as an interleukin-1-beta converting enzyme inhibitor
JP2001502330A (ja) * 1996-10-11 2001-02-20 ワーナー―ランバート・コンパニー スルホンアミド置換アスパラギン酸インターロイキン―１β変換酵素阻害剤
GB9621985D0 (en) 1996-10-22 1996-12-18 Peptide Therapeutics Ltd A solid-phase technology for the preparation of libraries of bi-directally functionalised drug-like molecules
US5877197A (en) * 1996-12-16 1999-03-02 Karanewsky; Donald S. C-terminal modified (N-substituted)-2-indolyl dipeptides as inhibitors of the ICE/ced-3 family of cysteine proteases
US6184244B1 (en) 1996-12-16 2001-02-06 Idun Pharmaceuticals, Inc. C-terminal modified (N-substituted)-2-indolyl dipeptides as inhibitors of the ICE/ced-3 family of cysteine proteases
US6054487A (en) * 1997-03-18 2000-04-25 Basf Aktiengesellschaft Methods and compositions for modulating responsiveness to corticosteroids
HUP9700816A3 (en) * 1997-04-28 1999-06-28 Gyogyszerkutato Intezet 3(r)-3-amino-4-carboxy-butiraldehyde derivatives inhibiting release of interleukin-1-beta
US6184210B1 (en) 1997-10-10 2001-02-06 Cytovia, Inc. Dipeptide apoptosis inhibitors and the use thereof
EP1033910A4 (de) * 1997-10-10 2004-11-24 Cytovia Inc Dipeptid-apoptose-inhibitoren und deren verwendung
EP1062210B1 (de) 1998-03-09 2005-06-01 Vertex Pharmaceuticals Incorporated 1,2-diazepanderivate als inhibitoren des interleukin-1beta umwandelnden enzyms
AU755273B2 (en) * 1998-03-16 2002-12-05 Cytovia, Inc. Dipeptide caspase inhibitors and the use thereof
PT1064298E (pt) * 1998-03-19 2009-01-02 Vertex Pharma Inibidores de caspasas
CN1148350C (zh) 1998-05-28 2004-05-05 拜奥根有限公司 新型VLA-4抑制剂:oMePUPA-V
US6432931B1 (en) 1998-06-24 2002-08-13 Merck & Co., Inc. Compositions and methods for inhibiting bone resorption
WO2000032620A1 (en) * 1998-12-02 2000-06-08 Merck Frosst Canada & Co. Gamma-ketoacid tetrapeptides as inhibitors of caspase-3
CA2367340A1 (en) 1999-03-16 2000-09-21 Cytovia, Inc. Substituted 2-aminobenzamide caspase inhibitors and the use thereof
CN1176941C (zh) 1999-04-09 2004-11-24 西托维亚公司 Caspase抑制剂及其应用
JP2003508379A (ja) 1999-08-27 2003-03-04 サイトビア インコーポレイテッド 置換α−ヒドロキシ酸カスパーゼインヒビターおよびその使用
US6566338B1 (en) 1999-10-12 2003-05-20 Cytovia, Inc. Caspase inhibitors for the treatment and prevention of chemotherapy and radiation therapy induced cell death
US6875743B1 (en) 2000-11-28 2005-04-05 Biogen, Inc. Cell adhesion inhibitors
AU2003211052A1 (en) * 2002-02-11 2003-09-04 Vertex Pharmaceuticals Incorporated Phospholipids as caspase inhibitor prodrugs
AU2005249503B2 (en) * 2003-11-10 2011-08-25 Vertex Pharmaceuticals Incorporated ICE inhibitors for the treatment of autoinflammatory diseases
GB0411056D0 (en) 2004-05-18 2004-06-23 Novartis Ag Organic compounds
WO2012061785A2 (en) 2010-11-05 2012-05-10 Brandeis University Ice inhibiting compounds and uses thereof
US9956260B1 (en) 2011-07-22 2018-05-01 The J. David Gladstone Institutes Treatment of HIV-1 infection and AIDS
CA3026074A1 (en) 2016-06-01 2017-12-07 M3 Biotechnology, Inc. N-hexanoic-l-tyrosine-l-isoleucine-(6)-aminohexanoic amide compounds and their use to treat neurodegenerative diseases

Family Cites Families (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4582821A (en) * 1983-11-16 1986-04-15 E. I. Du Pont De Nemours And Company Inhibition of cyclic nucleotide independent protein kinases
EP0263202A1 (de) * 1986-10-06 1988-04-13 E.I. Du Pont De Nemours And Company Hemmung von viraler Proteasewirkung durch Peptide der Halomethyl-Ketone
JPH0637987B2 (ja) * 1986-02-19 1994-05-18 松下精工株式会社 空気調和機の外装板取付装置
US5055451A (en) * 1986-12-22 1991-10-08 Syntex Inc. Aryloxy and arylacyloxy methyl ketones as thiol protease inhibitors
JPH0794418B2 (ja) * 1987-08-03 1995-10-11 和光純薬工業株式会社 新規な製造方法
WO1991015577A1 (en) * 1990-04-04 1991-10-17 Black, Roy, A. INTERLEUKIN 1'beta' PROTEASE
US5278061A (en) * 1991-08-16 1994-01-11 Merck & Co., Inc. Affinity chromatography matrix useful in purifying interleukin-1β converting enzyme
GB9123326D0 (en) * 1991-11-04 1991-12-18 Sandoz Ltd Improvements in or relating to organic compounds

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7034043B2 (en) 1999-08-13 2006-04-25 Biogen Idec Ma Inc. Cell adhesion inhibitors
US7417029B2 (en) 2000-05-19 2008-08-26 Vertex Pharmaceuticals Incorporated Prodrug of an ice inhibitor
US8022041B2 (en) 2000-05-19 2011-09-20 Vertex Pharmaceuticals Incorporated Prodrug of an ICE inhibitor
US8329662B2 (en) 2000-05-19 2012-12-11 Vertexd Pharmaceuticals Incorporated Prodrug of an ICE inhibitor
US9487555B2 (en) 2000-05-19 2016-11-08 Vertex Pharmaceuticals Incorporated Prodrug of an ice inhibitor
US7196112B2 (en) 2004-07-16 2007-03-27 Biogen Idec Ma Inc. Cell adhesion inhibitors

Also Published As

Publication number Publication date
EP0519748A3 (en) 1993-05-05
CA2071674C (en) 2003-08-19
JPH06102642B2 (ja) 1994-12-14
DE69226820T2 (de) 1999-05-12
US5434248A (en) 1995-07-18
DE69226820D1 (de) 1998-10-08
JPH05255218A (ja) 1993-10-05
EP0519748A2 (de) 1992-12-23
CA2071674A1 (en) 1992-12-22

Similar Documents

Publication Publication Date Title
EP0519748B1 (de) Peptidylderivate als Inhibitoren von Interleukin-1B-konvertierenden Enzymen
EP0627926B1 (de) Peptidylderivate und inhibitoren des interleukin-1-g(b)-konvertierenden enzyms
US5866545A (en) Substituted ketone derivatives as inhibitors of interleukin-1β converting enzyme
EP0547699A1 (de) Peptidylderivate als Inhibitoren von Interleukin-1-Beta-konvertierenden Enzymen
US5552400A (en) Fused-bicyclic lactams as interleukin-1β converting enzyme inhibitors
WO1993014777A1 (en) PEPTIDYL DERIVATIVES AS INHIBITORS OF INTERLEUKIN-1β CONVERTING ENZYME
JP4009320B2 (ja) インターロイキン―１β変換酵素のインヒビター
US5976858A (en) Irreversible cysteine protease inhibitors containing vinyl groups conjugated to electron withdrawing groups
US5821262A (en) Hydroxamic acid derivatives as inhibitors of cytokine production
AU755273B2 (en) Dipeptide caspase inhibitors and the use thereof
US5670494A (en) N-(pyrimidinyl)-aspartic acid analogs as interleukin-1β converting enzyme inhibitors
US5739279A (en) Peptidyl 4-amino-2,2-difluoro-3-oxo-1,6-hexanedioic acid derivatives as antiinflammatory agents
JPH09503201A (ja) Ｔｎｆ−アルファ分泌の阻害剤
WO1992021360A1 (en) Substituted n-carboxyalkylpeptidyl derivatives as antidegenerative active agents
CA2312826C (en) Hemiasterlin analogs
FR2621317A1 (fr) Tripeptides doues de proprietes immunostimulantes et antimetastasiques et procede pour leur preparation
JPH05252950A (ja) インターロイキン１β変換酵素精製用アフィニティークロマトグラフィーマトリックス
AU1875601A (en) Ox(adi)azolyl-hydroxamic acids useful as procollagen c-proteinase inhibitors
US5432186A (en) Cyclic amino acid derivatives
US6376649B1 (en) Methods for the synthesis of α- hydroxy-β-amino acid and amide derivatives
AU752031B2 (en) Novel spiro compounds or salts thereof, agent for preventing and/or treating autoimmune diseases and AP-1 inhibitors containing the same
DE69833646T2 (de) (3r)-3-amino-4-carboxybutyraldehydderivate die die il-1/beta freisetzung inhibieren
JPH07173142A (ja) ３（ｓ）−アミノ−４−シクロヘキシル−２（ｒ）−ヒドロキシ−酪酸又は４−シクロヘキシル−（２ｒ，３ｓ）−ジヒドロキシ−酪酸又は関連同族体を含む環状レニン阻害剤
US6613880B2 (en) Pipecolic acid derivatives of proline threonine amides useful for the treatment of rheumatoid arthritis

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

AK Designated contracting states

Kind code of ref document: A2

Designated state(s): CH DE FR GB IT LI NL

PUAL Search report despatched

Free format text: ORIGINAL CODE: 0009013

AK Designated contracting states

Kind code of ref document: A3

Designated state(s): CH DE FR GB IT LI NL

17P Request for examination filed

Effective date: 19931008

17Q First examination report despatched

Effective date: 19950822

GRAG Despatch of communication of intention to grant

Free format text: ORIGINAL CODE: EPIDOS AGRA

GRAG Despatch of communication of intention to grant

Free format text: ORIGINAL CODE: EPIDOS AGRA

GRAH Despatch of communication of intention to grant a patent

Free format text: ORIGINAL CODE: EPIDOS IGRA

GRAH Despatch of communication of intention to grant a patent

Free format text: ORIGINAL CODE: EPIDOS IGRA

GRAA (expected) grant

Free format text: ORIGINAL CODE: 0009210

ITF It: translation for a ep patent filed

Owner name: SOCIETA' ITALIANA BREVETTI S.P.A.

AK Designated contracting states

Kind code of ref document: B1

Designated state(s): CH DE FR GB IT LI NL

REG Reference to a national code

Ref country code: CH

Ref legal event code: NV

Representative=s name: E. BLUM & CO. PATENTANWAELTE

Ref country code: CH

Ref legal event code: EP

REF Corresponds to:

Ref document number: 69226820

Country of ref document: DE

Date of ref document: 19981008

ET Fr: translation filed
PLBE No opposition filed within time limit

Free format text: ORIGINAL CODE: 0009261

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: NO OPPOSITION FILED WITHIN TIME LIMIT

26N No opposition filed
REG Reference to a national code

Ref country code: GB

Ref legal event code: IF02

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: GB

Payment date: 20030501

Year of fee payment: 12

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: NL

Payment date: 20030513

Year of fee payment: 12

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: FR

Payment date: 20030602

Year of fee payment: 12

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: CH

Payment date: 20030605

Year of fee payment: 12

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: DE

Payment date: 20030630

Year of fee payment: 12

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: GB

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20040619

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: LI

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20040630

Ref country code: CH

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20040630

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: NL

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20050101

Ref country code: DE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20050101

GBPC Gb: european patent ceased through non-payment of renewal fee

Effective date: 20040619

REG Reference to a national code

Ref country code: CH

Ref legal event code: PL

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: FR

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20050228

NLV4 Nl: lapsed or anulled due to non-payment of the annual fee

Effective date: 20050101

REG Reference to a national code

Ref country code: FR

Ref legal event code: ST

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: IT

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES;WARNING: LAPSES OF ITALIAN PATENTS WITH EFFECTIVE DATE BEFORE 2007 MAY HAVE OCCURRED AT ANY TIME BEFORE 2007. THE CORRECT EFFECTIVE DATE MAY BE DIFFERENT FROM THE ONE RECORDED.

Effective date: 20050619